A Road Map for Success in RCC

SAN FRANCISCO -- Renal cell carcinoma (RCC) had a mix of highs and lows over the past decade, and shifting the balance to the high side requires more emphasis on molecular biology and genetics, a clinician and investigator said here.

Therapy and patient care made "incredible" advances, but a cure for RCC remains out of reach at least for the time being, owing in no small part to the lack of predictive biomarkers for the disease, said Primo Lara Jr., MD, at the Genitourinary Cancers Symposium.

Unfortunately, the advances have contributed to a cost-prohibitive therapeutic milieu, as "me too" drugs have dominated drug development, he added.

"We have a road map for success," said Lara, of the University of California Davis. "We must use biology to guide drug development. We must design rational clinical trials; to use a football analogy, only forward passes, no laterals. We must increase access and cost effectiveness."

Admitting to a fondness for lists, Lara organized his review of the decade in RCC into two "Top 5" lists: the top five successes and top five disappointments.

Beginning with the successes, Lara said clinicians and research have developed a "blueprint of RCC biology," which includes comprehensive molecular characterization of clear-cell carcinoma, identification of factors associated with better and worse survival, and confirmation of clear-cell RCC as a metabolic disease.

Another success has come in the form of rapid drug development, seven new therapies since 2005, which Lara characterized as an "embarrassment of riches," as compared with therapeutic options before that year. Accrual to clinical trials has improved dramatically.

Much of the credit has to go to the pharmaceutical industry, which has sponsored a majority of trials, Lara said. In contrast, few publicly funded, high-impact trials have been conducted.

The embarrassment of riches is not without qualifiers.

"We have limited drug diversity," Lara said. "The drugs are not necessarily applicable to all histologies, and they are generally for favorable- and intermediate-risk only. The one exception is temsirolimus for poor-risk patients.

"We have yet to identify the optimal sequence for the therapies."

Moreover, the pride in new-drug development has to be tempered by a "recent run of bad luck," which has seen a half dozen or more failed phase III trials in RCC, he added.

Improved patient care also made the list of successes, as clinical trials have yielded improvements in response rate, progression-free survival (PFS), and overall survival.

"Progression-free survival has emerged as the global regulatory standard, although one must recognize the limitations of PFS," Lara said."Overall survival has proven too difficult to improve and has been relegated to secondary-endpoint status. However, it is still very relevant."

Several advances in nephron-sparing surgery occurred over the past decade, although the advances have limited support from phase III clinical trials.

Rounding out Lara's list of successes is the emergence of multidisciplinary collaboration in the care of patients with RCC. Urologists and medical oncologists interact in clinical settings or on tumor boards, and clinical trials have fostered development of unique surgical and medical collaborations.

Topping the list of disappointments is the failure to find a cure, at least for metastatic RCC. Targeted therapies rarely achieve complete responses, which might be assumed as the "first step to cure," and rates of partial responses are fairly modest -- 30% with angiogenesis inhibitors and less than 10% with inhibitors of mammalian target of rapamycin.

"The results are not surprising," Lara said. "Targeted therapies do not target the drivers of the disease. When true drivers are targeted, response rates greater than 70% will occur."

The absence of predictive biomarkers ranked second on the list of disappointments. One result is that "targeted" therapies are used in a nontargeted manner. The heterogeneity of the disease has thus far confounded attempts to identify clinically useful biomarkers, Lara said.

Related to the lack of cure is the inability to identify molecular drivers of RCC that are druggable, the third disappointment of the past decade.

"The phenotypic consequences of Von Hippel-Lindau disruption were described in the early 20th century," Lara said. "The VHL gene was mapped to chromosome 3 and associated with RCC in 1988. Yet, we still have no true VHL-targeted therapy."

The failure of combination therapy ranked fourth of Lara's list of disappointments. Clinicians and researchers had hoped that combination therapy would lead to higher response rates, therapeutic synergy, or at least additive activity, avoidance of cross-resistance, and replicate the success in hematologic and germ-cell cancers.

The reality is that combination therapy has increased toxicity as it achieved marginal improvement in efficacy, or none at all, and is more expensive, Lara said. The only approved combination is bevacizumab (Avastin) and interferon, which has virtually no usage and perpetuates use of interferon.

The fifth disappointment has been the rising cost of care and persistent limitations on access to care. Lara pointed out that interferon is still widely used in some countries, and availability of new agents remains uneven. Third-party coverage is inconsistent, and treatment guidelines vary from one region to another.

Progress toward achieving a cure for RCC in the next decade will require use of available blueprints, such as the molecular profile of hereditary and sporadic RCC, Lara said. The search for druggable targets must continue. Disease drivers must be identified and "passengers" have to be weeded out. New agents must be developed to target subclone disease drivers.

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